We will investigate the structural basis for receptor selectivity of members of the corticotropin releasing factor (CRF) that acts on widely distributed CRF receptors (CRFR1 and CRFR2) to produce a spectrum of specific central and peripheral biological/physiological effects. Based on preliminary results, we know that intramolecular bridges (i, i+3) spanning residues (i.e. lactum rings encompassing residues 30-33, 31-32 and 32-35. Once optimal bridges are identified, we hypothesize that amino acids will be identified that can be deleted without affecting activity or potency (a successful strategy applied in the design of somatostatin and NPY analogs). Peptides will be screened in vitro (binding to cloned receptors) (Project I). Selected analogs will be tested also in the rat anterior pituitary assay (Project I) and in vivo (Project V). Tertiary of the mot constrained CRF analogs will be determined with circular dichroism, nuclear magnetic resonance and computer simulations in order to understand peptide/receptor interactions. In collaborations with members of this program project, and outside investigators, we will determine the usefulness of selected analogs in animals to treat, manage, or identify the etiology of, a number of pathophysiological states. Because of structural similarities between growth hormone releasing factor (GRF) and CRF and between their respective receptors, we will attempt similar strategies in the design of GRF antagonists. Finally, bioactive peptides characterized by Project I, outside collaborators and Core C will be synthesized and preliminary SAR (such as determination of bioactive core) will be carried out.